The use of elevated ferritin levels in neonates and young infants as a screening lab for HLH

Abstract

Hemophagocytic lymphohistiocytosis (HLH) is a hyperinflammatory state due to primary genetic defect in T/NK cell cytotoxicity or secondary to infection, rheumatologic process, or malignancy. Activated macrophages/cytotoxic lymphocytes lead to elevated cytokines and T-cell activation. Ferritin is a screening tool, with levels >10,000 mug/L reported to be 90% sensitive and 96% specific for HLH. Its use in neonatal/early infancy hasn’t been specifically evaluated.In our retrospective case review we included patients 3 months or younger, treated in the past 5 years at our institution with an elevated ferritin >5000 mug/L. 20 patients were evaluated, demographic/diagnostic information seen in table 1. Average ferritin was 44 515 IQR (9922–54 853) Four patients, (20%) were diagnosed with primary HLH (pHLH), with non-HLH conditions including: 4 (20%) sepsis/infection, 4 (20%) with acute liver failure/galactosemia, 3 (15%) hematologic complications, and 5 (25%) without definitive diagnosis.All patients with HLH had splenomegaly and thrombocytopenia (< 100); 2 patients with pHLH had anemia (< 9), and 3 with ANC< 1000. Of those without HLH, 1 had splenomegaly, 9 with anemia, 6 with thrombocytopenia, and 1 with neutropenia. Soluble IL-2 receptor (sIL2R), a specific marker for T-cell activation was measured in 12 patients. pHLH patients had sIL2R levels >10 000 U/ml: pHLH average 31 432 (11 000–47 474), without pHLH average 2039 (1123–3161). sIL2R is more specific than ferritin but there are limitations (turn-around-time and locations performing). Figure 1 depicts ferritin/sIL2R levels in these groups.We utilized direct flow-based detection of T-cell activation markers for identification of HLH. As a proof of concept, patient 19 had fulminant HSV and a ferritin >200 000 mug/L. HLH diagnostic criteria were fulfilled, the T-cell activation profile was unremarkable (Figure 2). HLH treatment was not initiated; an unremarkable sIL2R result followed which validated our approach.A broad spectrum of etiologies drives high ferritin in neonatal/early infancy and can cause ferritin of >5000 mug/L. Thus, HLH 2004 criteria can be fulfilled in patients without pHLH resulting in inadvertent use of immune suppression. sIL2R and/or T-cell activation flow should be obtained when evaluating and initiating treatment for HLH. Further, genetic evaluation for other conditions is warranted in this patient population. [Display omitted] [Display omitted] Table 1(abstract: 128) Patient characteristics and information: laboratory values, genetics, and underlying diagnosis included.PatientPeak Ferritin (ng/ml)Large SpleenHgb (g/dL)Platelets (thou/ul)NCFibrinogen (mg/dl)SIL2R (units/ml)CXCL9 (pg/ml)PerforinCD107aGenetic FindingFinal DiagnosisCurrent Status127436+13.45042602761123N/ADecreasedLowNo definitive diagnosisUnknownAlive217491–10.43609700224N/N/AN/AN/ANon-contributoryABO incompatibilityAlive3106635–10809110132N/N/AN/AN/ANon-contributoryUnknownAlive482270–6.511540179N/N/AN/AN/AGALT, compound heterozygoteGalactosemiaDeceased59423N/A9.64010420621665N/AN/AN/AWES without definitive diagnosisUnknownAlive6150000+11.7632143024411,0006603N/ALowSTXBP2(homozygous)pHLHDeceased724304–11.91610480185N/AN/AN/AN/ANot collectedUnknownDeceased87494–8.841960603161N/AN/AN/APendingGalactosemiaAlive911412–9.1408770912144N/AN/AN/AWES without definitive diagnosisAcute liver failureAlive1014175–7.93721575173N/AN/AN/AN/ANo definitive diagnosisFulminant liver failureDeceased1117032–10.9332106023,000N/AAbsentPresentPRF1 (homozygous)pHLHDeceased12140000–5.52211880601644N/AN/AN/ANon-contributoryVitamin-K def hemorrhageDeceased139673–9.96992190216N/AN/AN/AN/ANon-contributoryCOVID-19 infectionAlive1410171–8.52952480N/2297N/AN/AN/ANot collectedViral hepatitisAlive155906–8.6103N/1081791N/AN/AN/ANot collectedCampylobacter bacteremiaAlive1614855+7.2101806844256325N/ALowRAB27A compound heterozygotepHLH, Griscelli SyndromeAlive179615–8.2263N/N/N/AN/AN/ALowIFIH1 heterozygous, pending further evaluationUnknownAlive1818730–7.61851940165N/AN/AN/AN/ANot collectedIntrauterine hydrops, secondary to Rh alloimmunization, liver failureAlive19>200000–6.3411400872493N/AN/AN/ATNFRSF13B HeterozygousHSV2 viremiaAlive2013675+6.8404506047474N/AN/ALowUNC13D, compound heterozygotepHLHDeceased